1. Field of the Invention
This application relates to anti-inflammatory agents. More specifically, the invention relates to compounds of the general formula (1), methods for their preparation, medicaments comprising these compounds, and their use for the treatment of humans and animals.
2. Background
According to a report in Morbidity and Mortality Weekly Report (MMWR 2007, 56, 423), arthritis and other rheumatic conditions, e.g., gout, lupus, and fibromyalgia, affect approximately 46 million adults in the United States, resulting in substantial disability and costs of $128 billion annually. The number of U.S. adults with doctor-diagnosed arthritis has been projected to reach nearly 67 million adults by the year 2030, including 25 million adults who are expected to have arthritis-attributable activity limitations. Among 48 states, the median projected increase in doctor-diagnosed arthritis from 2005 to 2030 will be 16%; a total of 14 states are projected to have increases of 30% to 87%.
The report further states that greater use of existing evidence-based interventions and development of new interventions aimed at decreasing pain, improving function, and delaying disability associated with arthritis are needed to reduce the impact of these projected increases, particularly in those states that will be most heavily affected. These statistics, together with recent studies that suggest links between chronic inflammation and many other disorders underscore the importance of anti-inflammatory drugs. Chronic inflammation may be the mediator for many adverse conditions ranging from allergies to serious health impairments such as atherosclerosis, cancer, osteoporosis, Alzheimer's disease and immune disorders such as myopathies, often in conjunction with others, for example systemic sclerosis, and include dermatomyositis, polymyositis, and inclusion body myositis.
There are now over a 100 medications being used in the treatment of arthritis and related conditions. Over-the-counter and prescription medications are the traditional treatment option for these diseases. With every response, inevitable drug side effects and adverse reactions to a specific medication are common and vary with the individual patient. In the attempt to minimize specific side effects, patients continually change their drug regimens and this need for change is reflected by such a large drug portfolio.
3. Overview of Pertinent Science and Biological Impact
The metabolites of arachidonic acid, such as prostaglandins, lipoxygenases, and thromboxanes are produced in many tissues and play an important role not only in many physiological events, but also in pathophysiological conditions, especially inflammation and cancer (Konturek P C, et al., J Physiol Pharmacol, 2005, 56 Suppl 5, 57-73). Cyclooxygenase-2 (COX-2) is an inducible form of prostaglandine-H synthase and mediates prostaglandin synthesis during inflammation. It is also overexpressed in certain tumors and ascribed to carcinogenic events, especially colon carcinogenesis (Kawamori T, et al., Cancer Research 1998, 58, 419-412).
The embodiment relates to new compounds of formula (1) as potent inhibitors of COX-2 activity in cell based assays. Said compounds, however, show relatively weak inhibitions of isolated COX-1, COX-2, and LOX enzymes. This property indicates that compounds of formula (1) inhibit the observed prostaglandin E-2 (PGE2) production in the cell-based assays of COX-2 by a mechanism that is beyond simple inhibition of the COX-2 enzyme. Although said compounds typically exhibited weaker activities than classic COX inhibitors in other COX-dependent models, they show very potent activities in the adjuvant-induced arthritis model in rats which indicates potential use for the treatment of rheumatoid arthritis and other chronic inflammatory conditions and diseases where inflammation is the underlying cause. This experimental model of polyarthritis is used widely for preclinical testing of anti-arthritic agents who are either under preclinical or clinical investigation or currently used as therapeutics in this disease (Pearson C M, Proc Soc Exp Biol Med 1956, 91, 95-100; Carlson R P, et al., Int J Immunopharmacol 1985, 7, 811; Benslay D N and Bendele A M, Agents Action 1991, 34, 254). Furthermore, the observed inhibition of COX-2-dependent PGE2 synthesis by compounds of formula (1) is particularly pronounced in human rheumatic synovial cells which is considered of relevance in human rheumatoid arthritis. These properties, together with a virtual absence of gastrointestinal liabilities, set the compounds of formula (1) apart from similar molecular entities which have been described previously. Compounds of the formula (1) are expected to afford a new category of anti-inflammatory drugs with utility as chemopreventive agents in oncology, asthma, neurodegenerative diseases and heart diseases.
4. Prior Art
The compounds that are subject to this embodiment are novel and the novelty of the compounds of formula (1) is underscored by the unprecedented biological properties outlined above. The most preferred compounds of this embodiment contain three significant structural features, namely a carboxamide, a pyrimidine ring, and either a 4-hydroxy-3,5-(ditert-butyl)phenyl or a 4,6-ditert-butyl-5-hydroxy-pyrimidin-2-yl moiety. These elements are independently present in known medications, including compounds with anti-inflammatory properties, but there is no precedent that combines all three in one molecule. Some of the more related drug candidates claim ion-channel modulatory properties, others claim Syk tyrosine kinase inhibition based on in vitro studies, still others claim anti-inflammatory activity, but those claims are merely based on cellular in vitro inhibition of certain transcription factors and chemokines. Unlike our embodiment, none of them actually demonstrate unmitigated anti-inflammatory activity by the reduction of swelling in a diseased joint of a warm-blooded animal and gastrointestinal drug tolerance. The following references are examples of drug candidates that contain the structural features mentioned above:
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